Anti-convulsant isoquinolyl-benzamide derivatives

ABSTRACT

Compounds of formula (I) and pharmaceutically acceptable salts thereof, where R 1  is hydrogen, C 1-6 alkyl (optionally substituted by hydroxy or C 1-4 alkoxy), C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 alkylCO—, formyl, CF 3 CO— or C 1-6 alkylSO 2 —; R 2  is hydrogen or up to three substituents selected from halogen, NO 2 , CN, N 3 , CF 3 O—, CF 3 S—, CF 3 CO—, trifluoromethyldiazirinyl, C 1-6?alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 perfluoroalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkyl-, C 1-6 alkylO—, C 1-6 alkylCO—, C 3-6 cycloalkylO—, C 3-6 cycloalkylCO—, C 3-6 cycloalkyl-C 1-4 alkylO—, C 3-6 cycloalkyl-C 1-4 alkylCO—, phenyl, phenoxy, benzyloxy, benzoyl, phenyl-C 1-4 alkyl-, C 1-6 alkylS—, C 1-6 alkylSO 2 —, (C 1-4 alkyl) 2 NSO 2 —, (C 1-4 alkyl)NHSO 2 —, (C 1-4 alkyl) 2 NCO—, (C 1-4 alkyl)NHCO— or CONH 2 ; or —NR 5 R 6  where R 5  is hydrogen or C 1-4 alkyl, and R 6  is hydrogen, C 1-4 alkyl, formyl, —CO 2 C 1-4 alkyl or —COC 1-4 alkyl; or two R 2  groups together form a carbocyclic ring that is saturated or unsaturated and unsubstituted or substituted by —OH or ═O; and the two R 3  groups and the two R 4  groups are each independently hydrogen or C 1-6 alkyl or the two R 3  groups and/or the two R 4  groups together form a C 3-6 spiroalkyl group provided that at least one R 3  and R 4  group is not hydrogen, are useful in the treatment and prophylaxis of epilepsy and other disorders.

This invention relates to novel compounds, to processes for preparingthem, and to their use as therapeutic agents. U.S. Pat. No. 4,022,900(Marion) discloses benzamido-tetrahydroisoquinolines havinganti-hypertensive and vasodilator properties.

WO97/48683 (Smithline Beecham), unpublished at the filing date of thisapplication, discloses that benzamide compounds of formula (A) belowpossess anticonvulsant activity and are therefore believed to be usefulin the treatment and/or prevention of anxiety, mania, and relateddepression disorders.

where n and p are independently integers from 1 to 4 and (n+p) is from 2to 5;

R¹ is C₁₋₆alkylO—;

R² is hydrogen, halogen, CN, N₃, trifluoromethyldiazirinyl, CF₃, CF₃O—,CF₃S—, CF₃CO—, C₁₋₆alkyl, C₃₋₆cycloalkyl,C₃₋₆cycloalkyl-C₁₋₄alkyl-,C₁₋₆alkylO—, C₁₋₆alkylCO—, C₃₋₆cycloalkylCO—,C₃₋₆cycloalkyl-C₁₋₄alkylCO—, phenyl, phenoxy, benzyloxy, benzoyl,phenyl-C₁₋₄alkyl-, C₁₋₆alkylS—, C₁₋₆alkylSO₂—, (C₁₋₄alkyl)₂NSO₂— or(C₁₋₄alkyl)NHSO₂—;

R³ is hydrogen, halogen, NO₂, CN, N₃, trifluoromethyldiazirinyl, C₁₋₆alkylO—, C₁₋₆ alkylS—, C₁₋₆ alkyl, C₃₋₆cycloalkyl,C₃₋₆cycloalkyl-C₁₋₄alkyl-, C₁₋₆alkenyl, C₁₋₆alkynyl, CF₃CO—,C₁₋₆alkylCO—, C₃₋₆cycloalkylCO—, C₃₋₆cycloalkyl-C₁₋₄alkylCO—, phenyl,phenoxy, benzyloxy, benzoyl, phenyl-C₁₋₄alkyl-, or —NR⁵R⁶ where R⁵ ishydrogen or C₁₋₄ alkyl, and R⁶ is hydrogen, C₁₋₄alkyl, —CHO,—CO₂C₁₋₄alkyl or —COC₁₋₄alkyl;

R⁴ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkenyl, or C₁₋₆ alkynyl.

It has now been surprisingly found that carboxamide compounds of formula(I) below possess anti-convulsant activity and are therefore believed tobe useful in the treatment and/or prevention of anxiety, mania,depression , panic disorders and/or aggression, disorders associatedwith a subarachnoid haemorrhage or neural shock, the effects associatedwith withdrawal from substances of abuse such as cocaine, nicotine,alcohol and benzodiazepines, disorders treatable and/or preventable withanti-convulsive agents, such as epilepsy including post-traumaticepilepsy, Parkinson's disease, psychosis, migraine, cerebral ischaemia,Alzheimer's disease and other degenerative diseases such as Huntingdon'schorea, schizophrenia, obsessive compulsive disorders (OCD),neurological deficits associated with AIDS, sleep disorders (includingcircadian rhythm disorders, insomnia & narcolepsy), tics (e.g. Giles dela Tourette's syndrome), traumatic brain injury, tirmitus, neuralgia,especially trigeminal neuralgia, neuropathic pain, dental pain, cancerpain, inappropriate neuronal activity resulting in neurodysthesias indiseases such as diabetes, multiple sclerosis (MS) and motor neuronedisease, ataxias, muscular rigidity (spasticity), temporomandibularjoint dysfunction, and amyotrophic lateral sclerosis (ALS).

Accordingly, the present invention provides a compound of formula (I) orpharmaceutically acceptable salt thereof:

where R¹ is hydrogen, C₁₋₆ alkyl (optionally substituted by hydroxy orC₁₋₄alkoxy), C₁₋₆alkenyl, C₁₋₆alkynyl, C₁₋₆alkylCO—, formyl, CF₃CO— orC₁₋₆alkylSO₂—,

R² is hydrogen or up to three substituents selected from halogen, NO₂,CN, N₃, CF₃O—, CF₃S—, CF₃CO—, trifluoromethyldiazirinyl, C₁₋₆alkyl,C₁₋₆alkenyl, C₁₋₆alkynyl, C₁₋₆perfluoroalkyl, C₃₋₆cycloalkyl,C₃₋₆cycloalkyl-C₁₋₄alkyl-, C₁₋₆alkylO—, C₁₋₆alkylCO—, C₃₋₆cycloalkylO—,C₃₋₆cycloalkylCO—, C₃₋₆cycloalkyl-C₁₋₄alkylO—,C₃₋₆cycloalkyl-C₁₋₄alkylCO—, phenyl, phenoxy, benzyloxy, benzoyl,phenyl-C₁₋₄alkyl-, C₁₋₆alkylS—, C₁₋₆alkylSO₂—, (C₁₋₄alkyl)₂NSO₂—,(C₁₋₄alkyl)NHSO₂—, (C₁₋₄alkyl)₂NCO—, (C₁₋₄alkyl)NHCO— or CONH₂;

or —NR⁵R⁶ where R⁵ is hydrogen or C₁₋₄ alkyl, and R⁶ is hydrogen,C₁₋₄alkyl, formyl, —CO₂C₁₋₄alkyl or —COC₁₋₄alkyl;

or two R² groups together form a carbocyclic ring that is saturated orunsaturated and unsubstituted or substituted by —OH or ═O; and

the two R³ groups and the two R⁴ groups are each independently hydrogenor C₁₋₆ alkyl or the two R³ groups and/or the two R⁴ groups togetherform a C₃₋₆ spiroalkyl group provided that at least one R³ and R⁴ groupis not hydrogen.

The compounds of this invention are typicallyisoquinolinyl-carboxamides, especially(tetrahydroisoquinolin-7-yl)carboxamides. The carboxamide moiety may bea benzamide. When two R² groups form a carbocyclic ring, this istypically a 5-7 membered ring, and the carboxamide moiety may be anaphthalene carboxamide or an indane or indanone carboxamide.

In the formula (I), alkyl groups, including alkyl groups that are partof other moieties, such as alkoxy or acyl, may be straight chain orbranched. Phenyl groups, including phenyl groups that are part of othermoieties, in R² may optionally be substituted with one or moreindependently selected halogen or C₁₋₆ alkyl, C₁₋₆ alkoxy or C₁₋₆alkylcarbonyl. Suitable C₃₋₆ cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl. Suitable halo substituentsinclude fluoro, chloro, iodo and bromo.

It should be appreciated that compounds of the present invention possesschiral centres and as such may exist in different enantiomeric forms,the present invention extends to each enantiomeric form and mixturesthereof including diastereoisomers and racemates.

One suitable group of compounds of this invention are of formula (IA)

where

R¹ is hydrogen, C₁₋₆ alkyl (optionally substituted by hydroxy orC₁₋₄alkoxy), C₁₋₆ alkenyl, C₁₋₆ alkynyl, formyl, C₁₋₆alkylCO,C₁₋₆alkylSO₂, or CF₃CO—;

R²² is C₁₋₆alkylO—, C₃₋₆cycloalkylO— or C₃₋₆cycloalkyl C₁₋₄alkylO—;

R²³ is hydrogen, halogen, CN, N₃, trifiuoromethyldiazirinyl,C₁₋₆perfluoroalkyl, CF₃O—, CF₃S—, CF₃CO—, C₁₋₆alkyl, C₃₋₆cycloalkyl,C₃₋₆cycloalkyl-C₁₋₄alkyl-, C₁₋₆alkylO—, C₁₋₆alkylCO—, C₃₋₆cycloalkylCO—,C₃₋₆cycloalkyl-C₁₋₄alkylCO—, phenyl, phenoxy, benzyloxy, benzoyl,phenyl-C₁₋₄alkyl-, C₁₋₆alkylS—, C₁₋₆alkylSO₂—, (C₁₋₄alkyl)₂NSO₂,(C₁₋₄alkyl)NHSO₂, (C₁₋₄alkyl)₂NCO—, (C₁₋₄alkyl)NHCO— or CONH₂;

R²⁴ is hydrogen, halogen, NO₂, CN, N₃, trifluoromethyldiazirinyl, C₁₋₆alkylO—, C₁₋₆ alkylS—, C₁₋₆ alkyl, C₃₋₆cycloalkyl,C₃₋₆cycloalkyl-C₁₋₄alkyl-, C₁₋₆alkenyl, C₁₋₆alkynyl, CF₃CO—,C₁₋₆alkylCO—, C₃₋₆cycloalkylCO—, C₃₋₆cycloalkyl-C₁₋₄alkylCO—, phenyl,phenoxy, benzyloxy, benzoyl, phenylC₁₋₄alkyl-;

or —NR⁵R⁶ where R⁵ is hydrogen or C₁₋₄ alkyl, and R⁶ is hydrogen,C₁₋₄alkyl, formyl, —CO₂C₁₋₄alkyl or —COC₁₋₄alkyl;

or R²³ and R²⁴ together form a carbocyclic ring that is unsaturated orsaturated and unsubstituted or substituted by carbonyl or hydroxyl;

R⁴ is C₁₋₆ alkyl.

Another suitable group is of formula (IB)

where R¹ is hydrogen, C₁₋₆ alkyl (optionally substituted by hydroxy orC₁₋₄alkoxy), C₁₋₆alkenyl, C₁₋₆alkynyl, C₁₋₆alkylCO—, formyl, CF₃CO— orC₁₋₆alkylSO₂—,

R² is hydrogen or up to three substituents selected from halogen, NO₂,CN, N₃, CF₃O—, CF₃S—, CF₃CO—, trifluoromethyldiazirinyl, C₁₋₆alkyl,C₁₋₆alkenyl, C₁₋₆alkynyl, C₁₋₆perfluoroalkyl, C₃₋₆cycloalkyl,C₃₋₆cycloalky-C₁₋₄alkyl-, C₁₋₆alkylO—, C₁₋₆alkylCO—, C₃₋₆cycloalkylO—,C₃₋₆cycloalkylCO—, C₃₋₆cycloalkyl-C₁₋₄alkylO—,C₃₋₆cycloalkyl-C₁₋₄alkylCO—, phenyl, phenoxy, benzyloxy, benzoyl,phenyl-C₁₋₄alkyl-, C₁₋₆alkylS—, C₁₋₆alkylSO₂—, (C₁₋₄alkyl)₂NSO₂—,(C₁₋₄alkyl)NHSO₂—, (C₁₋₄alkyl)₂NCO—, (C₁₋₄alkyl)NHCO— or CONH₂;

or —NR⁵R⁶ where R⁵ is hydrogen or C₁₋₄ alkyl, and R⁶ is hydrogen,C₁₋₄alkyl, formyl, —CO₂C₁₋₄alkyl or —COC₁₋₄alkyl;

or two R² groups together form a cabocyclic ring that is saturated orunsaturated and unsubstituted or substituted by —OH or ═O; and

each R³ is C₁₋₆ alkyl.

A further suitable group is of formula (IC)

where R¹ is hydrogen, C₁₋₆ alkyl (optionally substituted by hydroxy orC₁₋₄alkoxy), C₁₋₆alkenyl, C₁₋₆alkynyl, C₁₋₆alkylCO—, formyl, CF₃CO— orC₁₋₆alkylSO₂—,

R² is hydrogen or up to three substituents selected from halogen, NO₂,CN, N₃, CF₃O—, CF₃S—, CF₃CO—, trifluoromethyldiazirinyl, C₁₋₆alkyl,C₁₋₆alkenyl, C₁₋₆alkynyl, C₁₋₆perfluoroalkyl, C₃₋₆cycloalkyl,C₃₋₆cycloalkyl-C₁₋₄alkyl-, C₁₋₆alkylO—, C₁₋₆alkylCO—, C₃₋₆cycloalkylO—,C₃₋₆cycloalkylCO—, C₃₋₆cycloalkyl-C₁₋₄alkylO—,C₃₋₆cycloalkyl-C₁₋₄alkylCO—, phenyl, phenoxy, benzyloxy, benzoyl,phenyl-C₁₋₄alkyl-, C₁₋₆alkylS—, C₁₋₆alkylSO₂—, (C₁₋₄alkyl)₂NSO₂—,(C₁₋₄alkyl)NHSO₂—, (C₁₋₄alkyl)₂NCO—, (C₁₋₄alkyl)NHCO— or CONH₂;

or —NR⁵R⁶ where R⁵ is hydrogen or C₁₋₄ alkyl, and R⁶ is hydrogen,C₁₋₄alkyl, formyl, —CO₂C₁₋₄alkyl or —COC₁₋₄alkyl;

or two R² groups together form a carbocyclic ring that is saturated orunsaturated and unsubstituted or substituted by —OH or ═O; and

each R⁴ is C₁₋₆ alkyl.

A suitable group of compounds of formula (I), (IB) and (IC) have

R¹ as hydrogen, methyl, ethyl, propyl, hydroxyethyl, methoxyethyl,formyl, acetyl, trifluoroacetyl or methanesulfonyl,

R² as hydrogen or one or more of methyl, ethyl, n-butyl, iso-propyl,t-butyl, phenyl, methoxy, ethoxy, iso-propoxy, cyclopropylmethoxy,n-butoxy, phenoxy, benzyloxy, amino, acetylamino, nitro, azido, cyano,bromo, chloro, fluoro, iodo, acetyl, pivaloyl, iso-butyroyl, benzoyl,iodobenzoyl, trifluoromethyl, perfluoroethyl, trifluoromethoxy,trifluoroacetyl, methanesulfonyl, n-propylsulfonyl, isopropylsulfonyl,dimethylsulfamoyl,

R³ one or both is methyl,

R⁴ one or both is methyl.

In compounds of formula (IA) groups R¹ and R⁴ are suitably selected fromthe above list, and R²², R²³ and R²⁴ are selected as appropriate valuesfrom the above listing for R².

A preferred group of compounds of formula (I) have

R¹ as hydrogen, methyl, ethyl,

R² as hydrogen or one or more of methyl, ethyl, i-propyl, t-butyl,methoxy, ethoxy, i-propoxy, bromo, chloro, cyano, trifluoromethyl,

R³ one or both is methyl,

R⁴ one or both is methyl.

Examples of compounds of formula (I) are:

(±)N-(1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-4-ethoxy-2-methoxybenzamide

(±)N-(1,2-dimethyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-bromo-2,4-dimethoxybenzamide

(±)N-(1,2-dimethyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-4-ethoxy-2-methoxybenzamide

(±)N-(1,2-dimethyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-4-iso-propoxy-2-methoxybenzamide

(±)N-(1,2-dimethyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-tert-butyl-2-methoxybenzamide

(±) N-(1,2-dimethyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-trifluoromethyl-2-methoxy-4-methyl-benzamide

N-(2,4,4-trimethyl-4H-isoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide

N-(2,4,4-trimethyl-4H-isoquinolin-7-yl)-3-cyano-4-iso-propylbenzamide

N-(2,4,4,-trimethyl-4H-isoquinolin-7-yl)-3-bromo-4-ethylbenzamide

N-(2,4,4-trimethyl-4H-isoquinolin-7-yl)-3-bromo-4-ethoxybenzamide

N-(2,4,4-trimethyl-4H-isoquinolin-7-yl)-3-chloro-4-iso-propoxybenzamide

(±) N-(1,2-dimethyl-4H-isoquinolin-7-yl)-3-bromo-4-ethylbenzamide

(±) N-(1,2-dimethyl-4H-isoquinolin-7-yl)-3-bromo-4-ethoxybenzamide

N-(1,1,2-trimethyl-4H-isoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide

When synthesised, these compounds are often in salt form, such as thehydrochloride or trifluoroacetate, and such salts also form part of thisinvention. Such salts may be used in preparing pharmaceuticallyacceptable salts. The compounds and their salts may be obtained assolvates, such as hydrates, and these also form part of this invention.

The above compounds and pharmaceutically acceptable salts thereof,especially the hydrochloride, and pharmaceutically acceptable solvates,especially hydrates, form a preferred aspect of the present invention.

The administration of such compounds to a mammal may be by way of oral,parenteral, sublingual, nasal, rectal, topical or transdermaladministration.

An amount effective to treat the disorders hereinbefore describeddepends on the usual factors such as the nature and severity of thedisorders being treated and the weight of the mammal However, a unitdose will normally contain 1 to 1000 mg, suitably 1 to 500 mg, forexample an amount in the range of from 2 to 400 mg such as 2, 5, 10, 20,30, 40, 50, 100, 200, 300 and 400 mg of the active compound. Unit doseswill normally be administered once or more than once per day, forexample 1, 2, 3, 4, 5 or 6 times a day, more usually 1 to 4 times a day,such that the total daily dose is normally in the range, for a 70 kgadult of 1 to 1000 mg, for example 1 to 500 mg, that is in the range ofapproximately 0.01 to 15 mg/kg/day, more usually 0.1 to 6 mg/kg/day, forexample 1 to 6 mg/kg/day.

It is greatly preferred that the compound of formula (I) is administeredin the form of a unit-dose composition, such as a unit dose oral,including sub-lingual, rectal, topical or parenteral (especiallyintravenous) composition.

Such compositions are prepared by admixture and are suitably adapted fororal or parenteral administration, and as such may be in the form oftablets, capsules, oral liquid preparations, powders, granules,lozenges, reconstitutable powders, injectable and infusable solutions orsuspensions or suppositories. Orally administrable compositions arepreferred, in particular shaped oral compositions, since they are moreconvenient for general use.

Tablets and capsules for oral administration are usually presented in aunit dose, and contain conventional excipients such as binding agents,fillers, diluents, tabletting agents, lubricants, disintegrants,colorants, flavourings, and wetting agents. The tablets may be coatedaccording to well known methods in the art.

Suitable fillers for use include cellulose, mannitol, lactose and othersimilar agents. Suitable disintegrants include starch,polyvinylpyrrolidone and starch derivatives such as sodium starchglycollate. Suitable lubricants include, for example, magnesiumstearate. Suitable pharmaceutically acceptable wetting agents includesodium lauryl sulphate.

These solid oral compositions may be prepared by conventional methods ofblending, filling, tabletting or the like. Repeated blending operationsmay be used to distribute the active agent throughout those compositionsemploying large quantities of filers. Such operations are, of course,conventional in the art.

Oral liquid preparations may be in the form of, for example, aqueous oroily suspensions, solutions, emulsions, syrups, or elixirs, or may bepresented as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, for example sorbitol,syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel or hydrogenated edible fats,emulsifying agents, for example lecithin, sorbitan monooleate, oracacia; non-aqueous vehicles (which may include edible oils), forexample, almond oil, fractionated coconut oil, oily esters such asesters of glycerine, propylene glycol, or ethyl alcohol; preservatives,for example methyl or propyl p-hydroxybenzoate or sorbic acid, and ifdesired conventional flavouring or colouring agents. Oral formulationsalso include conventional sustained release formulations, such astablets or granules having an enteric coating.

For parenteral administration, fluid unit dose forms are preparedcontaining the compound and a sterile vehicle. The compound, dependingon the vehicle and the concentration, can be either suspended ordissolved. Parenteral solutions are normally prepared by dissolving thecompound in a vehicle and filter sterilising before filling into asuitable vial or ampoule and sealing. Advantageously, adjuvants such asa local anaesthetic, preservatives and buffering agents are alsodissolved in the vehicle. To enhance the stability, the composition canbe frozen after filling into the vial and the water removed undervacuum.

Parenteral suspensions are prepared in substantially the same mannerexcept that the compound is suspended in the vehicle instead of beingdissolved and sterilised by exposure to ethylene oxide before suspendingin the sterile vehicle. Advantageously, a surfactant or wetting agent isincluded in the composition to facilitate uniform distribution of thecompound of the invention.

As is common practice, the compositions will usually be accompanied bywritten or printed directions for use in the medical treatmentconcerned.

Accordingly, the present invention further provides a pharmaceuticalcomposition for use in the treatment and/or prophylaxis of anxiety,mania, depression, panic disorders and/or aggression, disordersassociated with a subarachnoid haemorrhage or neural shock, the effectsassociated with withdrawal from substances of abuse such as cocaine,nicotine, alcohol and benzodiazepines, disorders treatable and/orpreventable with anti-convulsive agents, such as epilepsy includingpost-traumatic epilepsy, Parkinson's disease, psychosis, migraine,cerebral ischaemia, Alzheimer's disease and other degenerative diseasessuch as Huntingdon's chorea, schizophrenia, obsessive compulsivedisorders (OCD), neurological deficits aosociated with AIDS, sleepdisorders (including circadian rhythm disorders, insomnia & narcolepsy),tics (e.g. Giles de la Tourette's syndrome), traumatic brain injury,tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain,dental pain, cancer pain, inappropriate neuronal activity resulting inneurodysthesias in diseases such as diabetes, multiple sclerosis (MS)and motor neurone disease, ataxias, muscular rigidity (spasticity),temporomandibular joint dysfunction, and amyotrophic lateral sclerosis(ALS) which comprises a compound of formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, and a pharmaceutically acceptablecarrier.

The present invention also provides a method of treatment and/orprophylaxis of anxiety, mania, depression, panic disorders and/oraggression, disorders associated with a subarachnoid haemorrhage orneural shock, the effects associated with withdrawal from substances ofabuse such as cocaine, nicotine, alcohol and benzodiazepines, disorderstreatable and/or preventable with anti-convulsive agents, such asepilepsy including post-traumatic epilepsy, Parkinson's disease,psychosis, migraine, cerebral ischaemia, Alzheimer's disease and otherdegenerative diseases such as Huntingdon's chorea, schizophrenia,obsessive compulsive disorders (OCD), neurological deficits associatedwith AIDS, sleep disorders (including circadian rhythm disorders,insomnia & narcolepsy), tics (e.g. Giles de la Tourette's syndrome),traumatic brain injury, tinnitus, neuralgia, especially trigeminalneuralgia, neuropathic pain, dental pain, cancer pain, inappropriateneuronal activity resulting in neurodysthesias in diseases such asdiabetes, multiple sclerosis (MS) and motor neurone disease, ataxias,muscular rigidity (spasticity), temporomandibular joint dysfunction, andamyotrophic lateral sclerosis (ALS) comprising administering to thesufferer in need thereof an effective or prophylactic amount of acompound of formula (I), or a pharmaceutically acceptable salt orsolvate thereof.

In a further aspect the invention provides the use of a compound offormula (I), or a pharmaceutically acceptable salt or solvate thereof,for the manufacture of a medicament for the treatment and/or prophylaxisof anxiety, mania, depression, panic disorders and/or aggression,disorders associated with a subarachnoid haemorrhage or neural shock,the effects associated with withdrawal from substances of abuse such ascocaine, nicotine, alcohol and benzodiazepines, disorders treatableand/or preventable with anti-convulsive agents, such as epilepsyincluding post-traumatic epilepsy, Parkinson's disease, psychosis,migraine, cerebral ischaemia, Alzheimer's disease and other degenerativediseases such as Huntingdon's chorea, schizophrenia, obsessivecompulsive disorders (OCD), neurological deficits associated with AIDS,sleep disorders (including circadian rhythm disorders, insomnia &narcolepsy), tics (e.g. Giles de la Tourette's syndrome), traumaticbrain injury, tinnitus, neuralgia, especially trigeminal neuralgia,neuropathic pain, dental pain, cancer pain, inappropriate neuronalactivity resulting in neurodysthesias in diseases such as diabetes,multiple sclerosis (MS) and motor neurone disease, ataxias, muscularrigidity (spasticity), temporomandibular joint dysfunction, andamyotrophic lateral sclerosis (ALS).

In a further aspect the invention provides the use of a compound offormula (I), or a pharmaceutically acceptable salt or solvate, thereofas a therapeutic agent, in particular for the treatment and/orprophylaxis of anxiety, mania, depression, panic disorders and/oraggression, disorders associated with a subarachnoid haemorrhage orneural shock, the effects associated with withdrawal from substances ofabuse such as cocaine, nicotine, alcohol and benzodiazepines, disorderstreatable and/or preventable with anti-convulsive agents, such asepilepsy including post-traumatic epilepsy, Parkinson's disease,psychosis, migraine, cerebral ischaemia, Alzheimer's disease and otherdegenerative diseases such as Huntingdon's chorea, schizophrenia,obsessive compulsive disorders (OCD), neurological deficits associatedwith AIDS, sleep disorders (including circadian rhythm disorders,insomnia & narcolepsy), tics (e.g. Giles de la Tourette's syndrome),traumatic brain injury, tinnitus, neuralgia, especially trigeminalneuralgia, neuropathic pain, dental pain, cancer pain, inappropriateneuronal activity resulting in neurodysthesias in diseases such asdiabetes, multiple sclerosis (MS) and motor neurone disease, ataxias,muscular rigidity (spasticity), temporomandibular joint dysfunction, andamyotrophic lateral sclerosis (ALS).

Another aspect of the invention is a process for the preparation ofcompounds of formula (II) (I) as herein before described which comprisesreacting a compound of formula (II)

where R^(1A), R^(3A), R^(4A) are R¹, R³, R⁴ as defined for formula (I)or a group or groups convertible to R¹, R³, R⁴

with a compound of formula (III)

 where Y is Cl or OH, and R^(2A) groups are independently R² as definedfor formula (I) or a group or groups convertible to R²,

 and where required converting an R^(1A), R^(2A), R^(3A), R^(4A) groupto a R¹, R², R³, R⁴ group, converting one R¹, R², R³, R⁴ group toanother R¹, R², R³, R⁴ group, or converting a salt product to the freebase or another pharmaceutically acceptable salt, or separating anyenantiomers, or converting a free base product to a pharmaceuticallyacceptable salt.

Reaction of a compound of formula (III) which is a benzoyl chloridederivative (Y═Cl) will lead directly to the hydrochloride Sal Suitablesolvents include ethyl acetate or dichloromethane, optionally in thepresence of a base such as triethylamine. When the compound of formula(III) is a benzoic acid derivative (Y═OH), conventional conditions forcondensation of aromatic acids with amines may be used, for examplereacting the components in a mixture ofethyl-(dimethylaminopropyl)-carbodiimide/hydroxybenzotriazole in asuitable inert solvent such as dimethyl formamide.

Conversions of an R^(1A), R^(2A), R^(3A), R^(4A) group to a R¹, R², R³,R⁴ group typically arise when a protecting group is needed during theabove coupling reaction or during the preparation of the reactants bythe procedures described below. Interconversion of one R¹, R², R³, R⁴group to another typically arises when one compound of formula (I) isused as the immediate precursor of another compound of formula (I) orwhen it is easier to introduce a more complex or reactive substituent atthe end of a synthetic sequence.

Compounds of formula (II) when R⁴=H or alkyl may be prepared from thecorresponding isoguinoline of formula (IV)

by reaction with a compound R^(1A)Z where Z is a leaving group such ashalogen, especially iodo, or tosylate to obtain an intermediate offormula (V)

which is reacted with an R^(4A) containing Grignard reagent underconventional conditions to obtain a dihydroisoquinoline of formula (VI)

which can be hydrogenated, for example using hydrogen and apalladium/activated carbon catalyst, to obtain a tetrahydroisoquinolineof formula (II) which is a precursor for compounds of formula (IA).

Alternatively the compound of formula (IV) may be a nitro-isoquinoline,and the nitro group is converted to an amino group in the hydrogenationstep.

When the intended R¹ is hydrogen, the N of the isoquinoline ispreferably protected conventionally, for example by making R^(1A)benzyl, or 4-methoxybenzyl during introduction of the R⁴ group via theGrignard reagent. Again protection is preferably provided prior toformation of the benzamide, for example by tert.-butoxycarbonyl and thendeprotected under standard conditions, for example using trifluoroaceticacid/methylene chloride.

Amino/nitro-isoquinolines of formulae (IV) and the reagents used arecommercially available, or can be prepared from commercially availablematerials using conventional procedures described in the literature (eg.I. W. Matheson et al, J. Med. Chem. 1973, 16, 332).

Compounds of formula (II) which are precursors for compounds of formula(IB) may be prepared from the corresponding nitro-isoquinoline dione offormula (VW) with di-R³ substitution, by converting the nitro group toamino by catalytic hydrogenation as above and subsequently removing thedione groups by reduction with diborane. The nitro-dione may be obtainedby treating a di-R³isoquinoline dione [prepared using the procedure ofH. Takechi et al., Synthesis. 1992, 778] with fuming nitric acid. R^(1A)groups may be introduced as described above.

Compounds of formula (II) which are precursors for compounds of formula(IC) may be prepared from the correspondingnitro-3,4-dihydroisoquinoline by reduction with tin (II) chloride to theamino compound followed by quaternisation with an R^(1A)-X halide andsubsequent treatment with an R⁴ Grignard reagent. Compounds of formula(II) where both R₄ are alkyl may be prepared from the corresponding1-alkyl-3,4-dihydroisoquinoline by nitration [using procedures by R. D.Larsen et al, J. Org. Chem., 1991 56 6034 and A. P. Venkov and S. S.Abeghe, Syn. Commun., 1996 26 127] followed by quaternisation andtreatment with an R⁴ Grignard reagent as described above.

Compounds of formula (III) may be prepared by further substitution ofcommercially available benzoic acid derivatives using conventionalprocedures, or by oxidation of corresponding substituted benzylalcohols. Alternatively benzoic acids can be prepared fromcorrepondingly substituted phenols, for example by formation of theacetate, conversion to an acetophenone and then to the desired acid.

Where the above described intermediates are novel compounds, they alsoform part of this invention.

The preparation of compounds of ftis invention is further illustrated bythe following Preparations, Descriptions and Examples. The utility ofcompounds of this invention is shown by the Pharmacological Data thatfollow the Examples.

DESCRIPTION 1 (±) 5-Amino-2-benzyl-1-methyl-1,2-dihydroisoquinoline

To solution of 5-aminoisoquinoline (15 g, 104 mmol) in acetone (400 ml)was added benzyl bromide (18.6 ml, 156 mmol). The mixture was stirred atroom temp for 2 h before the precipitate was filtered off affording anorange solid (8.64 g). A second crop (4.02 g) was filtered after afurther 2 h. To a solution of this 5-amino-2-benzyl-isoquinoliniumbromide (8.46 g, 26.8 mmol) in THF (75 ml) at 0° C. under argon wasadded dropwise methyl magnesium chloride (17.89 ml, 56.6 mmol). Themixture was allowed to warm up to room temperature and was stirred for 2h. The mixture was then poured into ammonium chloride solution andextracted with ether. The organic layer was dried over sodium sulfateand concentrated in vacuo to afford the title compound as a light brownsolid (5.0 g).

DESCRIPTION 2 (±) 5-Amino-1-methyl-1,2,3,4-tetrahydroisoquinoline

5-Amino-2-benzyl-1-methyl-1,2-dihydroisoquinoline (4.5 g, 17.9 mmol) wasdissolved in ethanol (250 ml); 10% palladium catalyst on activatedcarbon (1 g) was then added and the mixture hydrogenated at atmosphericpressure for 24 h. The catalyst was then removed by filtration throughKieselguhr and the solvent removed in vacuo to afford a brown solid.This residue was then subjected to column chromatography eluting with 5to 10% methanol-dichloromethane. The relevant fractions were combinedand concentrated in vacuo to afford a brown solid (1.26 g).

DESCRIPTION 3 (±)5-Amino-2-(t-butoxycarbonyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline

5-Amino-1-methyl-1,2,3,4-tetrahydroisoquinoline (0.39 g, 2.4 mmol) wasdissolved in 1,4-dioxane (25 ml) and sodium hydroxide solution (3M, 0.8ml) and cooled in an ice bath. The di-t-butyldicarbonate (0.53 g, 2.4mmol) was added and the mixture stirred at room temp for 2 h. Themixture was then poured into water and extracted with ether. The organiclayer was dried over sodium sulfate and concentrated in vacuo to afforda white solid. (0.251 g).

DESCRIPTION 4 (±) 5-Amino-1,2-dihydro-1,2-dimethylisoquinoline

5-Aminoisoquinoline (25 g, 173 mmol) was dissolved in acetone (500 ml)and methyl iodide (25 ml, 410 mmol) was added. After stirring at roomtemperature for 1 h the orange precipitate was filtered off, washed withacetone and dried in vacuo, affording an orange solid (40.3 g). A secondcrop was filtered off after 2 h affording an orange solid (0.84 g). To asolution of this 5-amino-2-methylisoqwnolinium iodide (21.013 g, 73.19mmol) in THF (150 ml) at 0° C. under argon was added methyl magnesiumchloride (36.6 ml 109.8 mmol) dropwise. The mixture was allowed to stirat room temperature for 2 h before being poured into ammonium chlorideand extracted with ether. The organic layer was dried over sodiumsulfate and concentrated in vacuo to afford a dark brown oil (8.52 g).

DESCRIPTION 5 (±) 5-Amino-1,2-dimethyl-1,2,3,4-tetrahydroisoquinoline

To an ice cold solution of 5-amino-1,2-dihydro-1,2-dimethyl isoquinoline(4 g, 23.2 mmol) in methanol (80 ml) was added sodium borohydride (3.51g, 92.8 mmol) portionwise. The mixture was allowed to stir at roomtemperature overnight before concentration in vacuo; the residue wasthen partitioned between water and dichloromethane. The organic layerwas dried over sodium sulfate and concentrated in vacuo to afford alight brown oil (4.023 g).

DESCRIPTION 6 7-Nitro-2,4,4-trimethyl-4H-isoquinoline-1,3-dione

2,4,4-Trimethyl-4H-isoquinoline-1,3-dione (5 g, 24.6 mmol) [preparedaccording to H. Takechi et al., Synthesis. 1992, 778] was dissolved inconcentrated sulfuric acid (50 ml) at 0° C. Fuming nitric acid (2.5 ml)was added dropwise over 5 min and the reaction warmed to 25° C. Afterstirring for 30 min at 25° C. the reaction mixture was poured into icewater (100 ml) and the organics extracted into dichloromethane (3×50ml). The combined organic extracts were dried over magnesium sulfate andevaporated in vacuo to give the title compound (5.31 g, 86%).

¹H NMR (250 MHz, CDCl₃) δ: 1.70 (6H, s), 3.42 (3H, s), 7.69 (1H, d, J=9Hz), 8.46 (1H, dd, J=9, 2 Hz), 9.07 (1H, d, J=2 Hz); m/z (API⁺): 249(M+H)⁺

DESCRIPTION 7 7-Amino-2,4,4,-trimethyl-4H-isoquinoline-1,3-dione

7-Nitro-2,4,4-trimethyl-4H-isoquinoline-1,3-dione (45 g, 20 mmol) wasdissolved in a methanol (500 ml)/dichloromethane (100 ml) mixture andtreated with 10% Pd/C (0.5 g). The reaction mixture was hydrogenated for2 h before removal of the palladium catalyst by filtration throughCelite. The filtrate was evaporated to dryness in vacuo to give thetitle compound (4.4 g, quant).

¹H NMR (250 MHz, CDCl₃) δ: 1.58 (6H, s), 3.36 (3H, s), 3.83 (2H, brs),6.95 (1H, dd,J=6, 3 Hz), 7.24 (1H, d, J=6 Hz), 7.48 (1H, d, J=3 Hz); m/z(API⁺): 219 (M+H)⁺

DESCRIPTION 8 7-Amino-2,4,4-trimethyl-4H-isoquinoline, hydrochloride

7-Amino-2,4,4-trimethyl-4H-isoquinoline-1,3-dione (4 g, 18.3 mmol) wasdissolved in tetrahydrofuran (400 ml) and heated at reflux (˜61° C.).Borone-tetrahydrofuran complex (88 ml, 1M solution in THF) was addeddropwise to the mixture and heating continued for a further 3 h. Thecooled reaction (0° C.) was treated with methanol (400 ml) dropwise todestroy residual borane, followed by evaporation in vacuo. The resultantresidue was heated at reflux in 3N HCl (400 ml) for 30 min. The mixturewas cooled to 0° C. and treated with NaOH pellets until basic (pH 9).The free amine was extracted into dichloromethane (4×100 ml) beforedrying over magnesium sulfate and evaporation in vacuo. The resultinglight brown oil was dissolved in dichloromethane (50 ml) and treatedwith hydrogen chloride (1M solution in ether) until acidic (pH 2).Solvent removal in vacuo followed by trituration with ether yielded thetitle compound as an off-white powder (3.3 g, 79%).

¹H NMR (free base 250 MHz, CDCl₃) δ: 1.25 (6H, s), 2.37 (2H, s), 2.39(3H, s), 3.43 (2H, s), 3.51 (2H, brs), 6.32 (1H, d, J=2 Hz), 6.54 (1H,dd, J=8, 2 Hz), 7.09 (1H, d, J=8 Hz); m/z (API⁺): 191 (M+H)⁺

DESCRIPTION 9 7-Anino-3,4-dihydroisoquinoline

7-Nitro-3,4-dihydroisoquinoline (0.60 g, 3.4 mmol) [prepared accordingto the procedure of A. P. Venkov et al, Syn. Commun., 1996 26 127] wasdissolved in ethanol (100 ml) and heated to 60° C. This hot solution wastreated with a solution of tin (II) chloride dihydrate (3.08 g, 13.7mmol) in conc. HCl (10 ml). The resultant mixture was heated at 60° for1 h. Upon cooling, the reaction mixture was poured into water (100 ml)and basified (pH 9) with KOH pellets, liberating an oily residue. Thisresidue was extracted into dichloromethane and dried over magnesiumsulfate. Purification by chromatography through silica gel, eluting with(0.5% conc. ammonia: 4.5% methanol: 95% dichloromethane) yielded thetitle compound as a dark yellow oil (0.44 g, 88%).

¹H NMR (250 MHz, CDCl₃) δ: 2.63 (2H, t, J=7 Hz), 3.67 (2H, brs), 3.73(2H, dt, J=7, 2 Hz), 6.62 (1H, d, J=2 Hz), 6.70 (1H, dd, J=8, 2 Hz),6.95 (1H, d, J=8 Hz), 8.24 (1H, s); m/z (API): 147 (M+H)⁺, 148 (M+2H)²⁺

DESCRIPTION 10 7-Amino-2-methyl-3,4-dihydroisoquinolinium iodide

7-amino-3,4-dihydroisoquinoline (0.40 g, 2.74 mmol) in acetone (125 ml)was treated with iodomethane (0.50 ml, 8.03 mmol) and left stirring atroom temperature for 18 h. The resultant yellow precipitate wascollected by filtration and dried in vacuo at ambient temperature (0.73g, 92%). m/z (API)=161 (M)⁺

DESCRIPTION 11 (±) 7-Amino-1,2-dimethyl-tetrahydroisoquinoline

(±) 7-Amino-2-methyl-3,4-dichloroisoquinolinium iodide (0.50 g, 1.7mmol) was suspended in anhydrous tetrahydrofuran (50 ml) and cooled to−78° C. The cooled solution was treated with methyl magnesium chloride(2.14 ml of a 3M solution in THF, 6.96 mmol), added as a single portion.The reaction was allowed to reach room temperature over 18 h beforebeing poured into water (50 ml). The organic solvent was removed invacuo and the organic product extracted into dichloromethane. Dryingover magnesium sulfate and evaporation in vacuo fuinished the titlecompound as a pale yellow oil (0.3 g, 98%). For ease of handling theproduct was converted into a monohydrochloride.

¹H NMR (250 MHz, CDCl₃) δ: 1.37 (3H, d, J=7 Hz), 2.46 (3H, s), 2.54-2.83(3H, m), 3.00 (1H, m), 3.50 (3H, m), 6.45 (1H, d, J=2 Hz), 6.51 (1H, dd,J=8, 2 Hz), 6.88 (1H, d, J=8 Hz); m/z, (API): 177 (M+H)⁺

DESCRIPTION 12 (±) 1-Methyl-7-nitro-3,4-dihydroisoquinoline

A solution of (±) 1-methyl-3,4-dihydroisoquinoline (2.57 g, 17.7 mmol)in conc. sulfuric acid (10 ml) was added dropwise to a stirred mixtureof potassium nitrate (1.93 g, 19.1 mmol) in conc. sulfuric acid (10 ml)at −5° C. The mixture was allowed to reach room temperature over 2 h andthen heated at 60° C. for 4 h. The reaction mixture was poured intoice-water (100 ml) and basified (pH 9) with KOH pellets. Extraction intodichloromethane (3×50 ml), drying over anhydrous sodium sulfate andevaporation in vacuo yielded the crude product. Purification bychromatography through silica gel, eluting with (0.5% 0.88 NH₃: 4.5%CH₃OH: 95% CH₂Cl₂) afforded the title compound as a dark brown oil (1.92g, 57%).

¹H NMR (250 MHz, CDCl₃) δ: 2.48 (3H, s), 2.82 (2H, t, J=8 Hz), 3.75 (2H,dt, J=8, 1 Hz), 7.38 (1H, d, J=8 Hz), 8.24 (1H, dd, J=8, 2 Hz), 8.33(1H, d, J=2 Hz). m/z (API): 191 (M+H)⁺

DESCRIPTION 13 (±) 7-Amino-1-methyl-3,4-dihydroisoquinoline

(±) 1-Methyl-7-nitro-3,4-dihydroisoquinoline (2.0 g, 10.5 mmol) wasdissolved in ethanol (150 ml) and heated to 60° C., before treatmentwith a solution of tin (II) chloride dihydrate (9.5 g, 42.1 mmol) inconc. HCl (30 ml). The resultant mixture was heated at 60° C. for 1 h.After cooling, the reaction mixture was poured into water (200 ml) andbasified (pH 9) with KOH pellets, liberating an oily residue. Thisresidue was extracted into dichloromethane and dried over magnesiumsulfate. Purification by chromatography through silica gel, eluting with(0.5% 0.88 NH₃: 4.5% CH₃OH: 95% CH₂Cl₂) yielded the title compound as adark brown oil (0.93 g, 55%).

¹H NMR (250 MHz, CDCl₃) δ: 2.35 (3H, s), 2.59 (2H, t, J=7 Hz), 3.62 (2H,t, J=7 Hz), 3.60 (2H, brs), 6.71 (1H, dd, J=8, 2 Hz), 6.83 (1H, d, J=2Hz), 6.98 (1H, d, J=8 Hz).

DESCRIPTION 14 (±) 7-Amino-1,2-dimethyl-3,4-dihydroisoquinolinium iodide

(±) 7-Amino-1-methyl-3,4-dihydroisoquinoline (0.90 g, 5.6 mmol) inacetone (125 ml) and iodomethane (1.0 ml, 16 mmol) was stirrd at roomtemperature for 18 h. The resultant precipitate was collected byfiltration and dried in vacuo at ambient temperature. The title compoundwas isolated as an orange powder (1.44 g, 85%). m/z (API): 175 (M)⁺

DESCRIPTION 15 7-Amino-1,1,2-trimethyl-1,2,3,4-tetrahydroisoquinoline

7-Amino-1,2-dimethyl-3,4-dihydroisoquinolinium iodide (1.44 g, 4.8 mmol)was suspended in THF (200 ml), cooled to −78° C. and treated with methylmagnesium chloride (10 ml of a 3M solution in THF) added as a singleportion. The reaction was allowed to reach room temperature over 18 hand poured into water (200 ml). The organic solvent was removed in vacuoand the resultant oily residue extracted into dichloromethane (3×50 ml).Evaporation in vacuo and chromatography through silica gel eluting with(0.5% 0.88 NH₃: 4.5% CH₃OH: 95% CH₂Cl₂) yielded the title compound as ayellow oil (0.07 g, 8%). For ease of handling the product was convertedinto a monohydrochloride.

¹H NMR (250 MHz, CDCl₃) δ: 1.45 (6H, s), 2.48 (3H, s), 2.80 (2H, t, J=6Hz), 2.96 (2H, t, J=6 Hz), 6.51 (1H, dd, J=8, 2 Hz), 6.57 (1H, d, J=2Hz), 6.86 (1H, d, J=8 Hz).

PREPARATION 1 Methyl 3-Chloro-4-iso-propoxybenzoate

Methyl 3-chloro-4-hydroxybenzoate (5 g, 26.8 mmol) in DMF (45 ml) wastreated with potassium carbonate (7.41 g, 53.6 mmol), 2-iodopropane(3.85 ml, 40.2 mmol) and then stirred at 25° C. for 18 h. Work-up withethyl acetate gave the title compound (6.1 g).

PREPARATION 2 3-Chloro-4-iso-propoxybenzoic acid

Methyl 3-chloro-4-isopropoxybenzoate (5.5 g, 24.1 mmol) was hydrolysedusing 1M NaOH (36 ml) in methanol (80 ml). Extraction and work-up withethyl acetate gave the title compound (4.3 g).

¹H NMR (DMSO) δ: 1.33 (6H, d), 4.79 (1H, m), 7.24 (5H, d), 7.87 (2H, m).

PREPARATION 3 3-Bromo-4-ethylbenzoic acid

The title compound was prepared from 4-ethylbenzoic acid in a mannersimilar to that of Procedure 1.

¹H NMR (DMSO) δ: 1.45 (3H, t, J=7 Hz), 4.26 (2H, q, J=7 Hz), 7.26 (1H,d, J=9 Hz), 7.98 (1H, dd, J=2, 9 Hz), 8.12 (1H, d, J=2 Hz).

PREPARATION 4 3-Bromo-4-ethylbenzoic acid

The title compound was prepared from 4-ethylbenzoic acid in a mannersimilar to that of Procedure 1.

¹H NMR (DMSO) δ: 1.20 (3H, t, J=7 Hz), 2.78 (2H, q, J=7 Hz), 7.50 (1H,d, J=8 Hz), 7.90 (1H, dd, J=2, 8 Hz), 8.07 (1H, d, J=8 Hz).

PREPARATION 5 3-Cyano-4-iso-propylbenzoic acid

The title compound was prepared from 4-iso-propylbenzoic acid using amanner similar to that described in Procedures 1 and 5.

¹H NMR (DMSO) δ: 1.07 (6H, d, J=7 Hz), 3.13 (1H,m, overlapped), 7.48(1H, d, J=7 Hz), 7.96 (1H, dd, J=2, 8 Hz)), 8.00 (1H, d, J=2 Hz).

PREPARATION 6 4-Methoxy-3-trifluoromethylbenzoic acid

The title compound was prepared from 3-bromo-4-methoxybenzoic acid andpotassium trifluoroacetate in a manner similar to that of Procedures 3and 4.

¹H NMR (DMSO) δ: 3.78 (3H, s), 7.18 (1H, d, J=9 Hz), 7.90 (1H, d, J=2Hz), 8.00 (1H, dd, J=2, 9 Hz), 12.70-13.10 (1H, br,exchangeable).

PREPARATION 7 4-Methoxy-3-trifluoromethylbenzoyl chloride

The title compound was prepared from 4-methoxy-3-trifluoromethylbenzoicacid with oxalkyl chloride and DMF in chloroform at room temperaturefollowed by evaporation in vacua.

PROCEDURE 1 5-Bromo-2,4-dimethoxybenzoic acid

To a solution of 2,4-dimethoxybenzoic acid (4.0 g, 0.022 mol) inchloroform (60 ml) was added bromine (1.13 ml, 0.022 mol) in chloroform(20 ml) dropwise. After stiring overnight at room temperature theprecipitate was filtered off and dried to afford the title compound as awhite solid (2.87 g).

PROCEDURE 2 5-Bromo-4-iso-propyl-2-methoxybenzoic acid

To a solution of 2-methoxy-4-iso-propyl benzoic acid (7.0 g, 36.0 mmol)in chloroform (100 ml) was added bromine (1.86 ml) in chloroform (20 ml)dropwise. The reaction was stirred at room temperature overnightEvaporation in vacuo afforded an oil (9.27 g). m/z (CI): 275, 273 (MH⁺;70%).

PROCEDURE 3 Methyl-5-bromo-4-iso-propyl-2-methoxy benzoate

5-Bromo-4-iso-propyl-2-methoxybenzoic acid (9.268 g 34.0 mmol) wasdissolved in ethanol (250 ml) and conc. H₂SO₄ (2 ml) added. The mixturewas refluxed for 5 h and concentrated in vacuo. Residual material wastaken up into ethyl acetate and water, and the organic layer, dried(MgSO₄). Concentration in vacuo afforded an oil, which was purified byBiotage Column Chromatography on silica gel using 10% ether in hexane togive an oil (5.5 g).

PROCEDURE 4 2,4-Dimethoxy-5-trifluoromethylbenzoic acid

2,4-Dimethoxy-5-bromobenzoic acid methyl ester (1.5 g; 5.4 mmol) in DMF(25 ml) and toluene (8 ml) under argon was treated with potassiumtrifluoroacetate (1.53 g; 10.1 mmol) and copper (I) iodide (2.1 g, 10.9mmol). The mixture was heated to 170° C. with removal of water(Dean/Stark), and then at 155° C. overnight. The mixture was allowed tocool, poured into ether and water and filtered through Kieselguhr. Theorganic layer was dried (Na₂SO₄) and concentrated in vacuo to give abrown solid. Chromatography on Kieselgel 60 with 1:1 ether/petrol gave awhite solid (1.03 g) which was hydrolysed in 1:1 methanolic: aqueousNaOH (50 ml) at 50° C. Work-up gave the title compound as a white solid(1 g).

PROCEDURE 5a Methyl 2-methoxy-5-cyano-4-iso-propylbenzoate

Copper (I) cyanide (550 mg, 6 mmol) was added to a solution of methyl2-methoxy-5-bromro-4-iso-propylbenzoate (861 mg) inN-methyl-2-pyrolidinone (30 ml). The mixture was stirred under argon andboiled under reflux for 4 h. The mixture was cooled, poured into excessice/water and ethyl acetate and filtered. The organic phase wasseparated, washed with water, brine and dried(MgSO₄). Evaporation gave acrude brown solid which was purified by chromatography on silica geleluting with ethyl acetate/n-hexane (1:4). The product was obtained as awhite solid (523 mg).

¹H NMR (250 MHz, CDCl₃) δ: 1.33 (6H, d, J=7 Hz), 3.38 (1H, sep, J=7 Hz),3.89 (3H, s), 3.98 (3H, s), 6.91 (1H, s), 8.08 (1H, s); m/z (API⁺): 234(MH⁺, 30%).

PROCEDURE 5b 2-Methoxy-5-cyano-4-iso-propylbenzoic acid

2N NaOH (1-25 ml) was added to a solution of the methyl ester P5a (490mg) in methanol (10 ml). The solution was stirred overnight at roomtemperature. The solution was then diluted with water, concentrated invacuo and washed with ethyl acetate. The aqueous phase was thenacidified with 2N HCl and extracted with ethyl acetate. The extract waswashed with brine, dried (MgSO₄) and evaporated to dryness giving theproduct as a white solid (418 mg).

¹H NMR (250 MHz, CDCl₃) δ: 1.35 (6H, d, J=7 Hz), 3.43 (1H, sep, J=7 Hz),4.14 (3H,s), 7.00 (1H, s), 8.41 (1H, s); m/z (API⁺): 220 (MH⁺, 100%).

PROCEDURE 6a Ethyl 2-ethoxy-4-iso-propyl-5-cyanobenzoate

Ethyl 2-ethoxy-4-iso-propyl-5-bromobenzoate (1.2 g, 3-8 mmol) wastreated with copper (I) cyanide (682 mg, 7.6 m.mol) inN-methyl-2-pyrrolidinone (40 ml) as described in Procedure 5 to give thetitle compound as an oil (400 mg).

¹H NMR (250 MHz, CDCl₃) δ: 1.12 (6H, d, J=7 Hz), 1.30 (3H, t, J=7 Hz),1.84 (3H, t, J=7 Hz), 3.17 (1H, sep, J=7 Hz), 3.99 (2H, q, J=9 Hz), 4.16(2H, q, J=7 Hz), 6.69 (1H, s), 7.86 (1H, s); m/z (API⁺): 262 (MH⁺,100%).

PROCEDURE 6b 2-Ethoxy-4-iso-propyl-5-cyanobenzoic acid

The ester P6a (370 mg, 1.41 mmol) was dissolved in methanol (5 ml) andover a 24 h period 1N NaOH (2.1 ml, 2.1 mmol) was added. The solutionwas concentrated under vacuum, diluted with water and washed with ethylacetate. The aqueous phase was acidified with 2N HCl and extracted withethyl acetate. The extract was washed with brine, dried (MgSO₄) andevaporated to give the title acid (306 mg).

¹H NMR (250 MHz CDCl₃) δ: 1.39 (3H, d, J=7 Hz), 1.66 (3H, t, J=7 Hz),3.47 (1H, sep, J=7 Hz), 4.46 (2H, q, J=7 Hz), 7.03 (1H, s), 8.47 (1H,s); m/z (API⁺): 234 (MH⁺, 100%).

PROCEDURE 7 4-Ethoxy-2-methoxy-5-methylsulfonylbenzoic acid

4-Ethoxy-2-methoxy-5-chlorosulfonyl benzoic acid in a 49% yield. wasprepared in 49% yield using the procedure of M. W. Harrold et al., J.Med. Chem., 1989, 32 874. This was used according to the method of R. W.Brown, J. Org. Chem., 1991, 56, 4974, to the title compound in 19%yield.

¹H NMR (DMSO) δ: 1.30 (3H, t), 3.10 (3H, s), 3.83 (3H, s), 4.24 (2H, q),6.73 (1H, s), 8.07 (1H, s).

PROCEDURE 8 4-iso-Propyl-2-methoxy-5-methylsulfonylbenzoic acid

This was prepared in a similar manner to the procedure of C. Hansch, B.Schmidhalter, F. Reiter, W. Saltonstall. J. Org. Chem., 1956, 21, 265 toafford the intermediate 5-chlorosulfonyl-4-isopropyl-2-methoxybenzoicacid which was converted into the title compound using the method ofProcedure 7.

¹H NMR (DMSO) δ: 1.30 (6H, d), 3.21 (3H, s), 3.80 (1H, m), 3.94 (3H, s),7.26 (1H, s), 8.19 (1H, s).

EXAMPLE 1 (a) (±)2-(t-Butoxycarbonyl)-N-(1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-4-ethoxy-2-methoxybenzamide

To a solution of5-amino-2-(t-butoxycarbonyl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline(0.251 g, 0.9 mmol) in dichloromethane (8 ml) and triethylamine (0.75ml) was added 5-chloro-4-ethoxy-2-methoxybenzoyl chloride (0.262 g, 1.05mmol) and the mixture stirred at room temperature overnight Afterdiluting with more dichloromethane, the mixture was washed with sodiumbicarbonate solution. The organic layer was dried over sodium sulfateand concentrated in vacuo to afford a beige solid. This was thenrecrystalised from ethyl acetate and petrol to afford a white solid.(0.124 g).

(b) (±)N-(1-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-4-ethoxy-2-methoxybenzamide,trifluoroacetate

To a solution of the above boc protected compound (0.124 g, 0.47 mmol)in dichloromethane (5 ml) at 0° C. was added trifluoroacetic acid (0.37ml) dropwise. The solution was stirred at room temperature for 3 h andthen the solvent was removed in vacuo to afford a beige solid (0.192 g).

¹H NMR (DMSO-d⁶) δ: 1.42 (3H, t, J=6 Hz), 1.60 (3H, d, J=6 Hz), 2.94(2H, m), 3.48 (2H, m), 4.08 (3H, s), 4.28 (2H, m), 6.95 (1H, s), 7.19(1H, d, J=6 Hz), 7.32 (1H, t, J=6 Hz), 7.28 (1H, d, J=6 Hz), 7.48 (1H,s), 9.00 (1H, m), 9.30 (1H, m), 9.73 (1H, s); m/z (CI): 375 (MH⁺)

EXAMPLE 2 (±)N-(1,2-Dimethyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-bromo-2,4-dimethoxybenzamide,hydrochloride

The title compound was prepared in a similar fashion to Example 1 from5-amino-1,2-dimethyl-1,2,3,4-tetrahydroisoquinoline and2,4-dimethoxy-5-bromobenzoic acid. The crude product was recrystallisedfrom methanol and ethyl acetate to afford a white solid (101 mg).

¹H NMR (DMSO-d⁶) δ: 1.62 (3H, m), 2.85 (3H, br.s), 3.00 (2H, m), 3.18(2H, s), 4.02 (3H, s), 4.12 (3H, s), 4.63 (1H, m), 6.93 (1H, s), 7.15(1H, d, J=6 Hz), 7.35 (1H, t, J=6 Hz), 7.88 (1H, d, J=6 Hz), 8.09 (1H,s), 9.75 (1H, s), 10.91 (1H, br.s); m/z (CI): 419 (MH⁺)

EXAMPLE 3 (±)N-(1,2-Dimethyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-4-ethoxy-2-methoxybenzamide,hydrochloride

The title compound was prepared in a similar fashion to Example 1 from5-amino-1,2-dimethyl-1,2,3,4-tetrahydroisoquinoline and5-chloro-4-ethoxy-2-methoxybenzoic acid. The crude product wasrecrystallised from methanol and ethyl acetate to afford a pale brownsolid (319 mg).

¹H NMR (DMSO-d⁶) δ: 1.42 (3H, t, J=6 Hz), 1.56 (1H, d, J=6 Hz), 1.70(2H, d, J=6 Hz) 2.80 (2H, m), 3.03 (2H, m), 3.32-3.62 (3H, m), 4.09 (3H,s), 4.29 (2H, m), 4.65 (1H, m), 6.96 (1H, s), 7.12 (1H, m), 7.35 (1H, t,J=6 Hz), 7.90 (2H, m), 9.25 (1H, m), 11.42 (1H, br.s); m/z (CI): 389(MH⁺)

The following Examples were prepared using methods similar to thoseoutline above.

EXAMPLE 4 (±)N-(1,2-Dimethyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-4-iso-propoxy-2-methoxybenzamide,hydrochloride

¹H NMR (DMSO-d⁶) δ: 1.32 (6H, d), 1.6 (3H, m), 2.66 (3H, m), 3.02 (2H,m), 3.58 (2H, m), 4.04 (3H, s), 4.60 (1H, m), 4.97 (1H, m), 7.17-7.90(5H, m), 9.75 (1H, m), 11.30 (1H, br s); m/z (CI): 403 (MH⁺).

EXAMPLE 5 (±)N-(1,2-Dimethyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-tert-butyl-2-methoxybenzamide,hydrochloride

¹H NMR (DMSO-d⁶) δ: 1.32 (9H, s), 1.61 (3H, m), 2.82 (3H, m), 3.07 (2H,m), 3.50 (2H, m), 4.05 (3H, s), 4.64 (1H, m), 7.12 (3H, m), 7.34 (1H,m), 7.88 (2H, m), 9.85 (1H, br s), 11.08 (1H, br s); m/z (CI): 367(MH⁺).

EXAMPLE 6 (±)N-(1,2-Dimethyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-trifluoromethyl-2-methoxy-4-methylbenzamide, hydrochloride

¹H NMR (DMSO-d⁶) δ: 1.60 (4H, m), 2.80 (4H, m), 3.00 (2H, m), 3.50 (3H,m), 4.06 (3H, s), 4.55 (1H, m), 7.20 (3H, m), 7.73 (1H, m), 8.08 (1H,m), 9.81 (1H, m), 11.27 (1H, m); m/z (CI): 393 (MH⁺).

EXAMPLE 7N-(2,4,4-Trimethyl-4H-isoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide,hydrochloride

The amine hydrochloride D8 (226 mg, 1.0 mmol) in dichloromethane (10 ml)was sequentially treated with 4-methoxy-3-trifluoromethylbenzoylchloride (283 mg, 1.0 mmol) and triethylamine (0.4 ml, 2.9 mmol). Themixture was stirred at 25° C. for 18 h and evaporated in vacuo. Theresultant residue was purified by chromatography on silica gel elutingwith dichloromethane:ammonia:methanol (0.5% conc. ammonia: 4.5%methanol: 95% dichloromethane). The title compound was obtained as anoff-white foam (337 mg, 86%) which was converted into the hydrochloride.

¹H NMR (250 MHz, d⁶DMSO) δ: 1.26 (3H, s), 1.37 (3H, s), 2.43 (5H,overlapping DMSO), 3.91 (3H, s), 4.30 (2H, m), 7.36 (1H, d, J=9 Hz),7.42 (1H, d, J=9 Hz), 7.58 (2H, m), 8.18 (1H, s), 8.23 (1H, d, J=9 Hz),9.80 (1H, brs); m/z (API⁺): 393 (M+H)⁺

EXAMPLE 8N-(2,4,4-Trimethyl-4H-isoquinolin-7-yl)-3-cyano-4-iso-propylbenzamide

Prepared in a similar manner to Example 7, using3-cyano-4-iso-propylbenzoyl chloride, and isolated in 70% yield.

¹H NMR (250 MHz, CDCl₃) δ: 1.31 (6H, s), 1.35 (6H, d, J=7 Hz), 2.40 (2H,s), 2.42 (3H, s), 3.44 (1H, m), 3.55 (2H, s), 7.37 (3H, s), 7.53 (1H, d,J=8 Hz), 7.67 (1H, brs), 8.02 (1H, d, J=2 Hz), 8.09 (1H, d, J=2 Hz); m/z(API⁺): 362 (M+H)⁺

EXAMPLE 9N-(2,4,4,-Trimethyl-4H-isoquinolin-7-yl)-3-bromo-4-ethylbenzamide

Prepared in a similar manner to Example 7, using 3-bromo-4-ethylbenzoylchloride, and isolated in 89% yield.

¹H NMR (250 MHz, CDCl₃) δ: 1.26 (3H, t, J=8 Hz), 1.30 (6H, s), 2.39 (2H,s), 2.42 (3H, s), 2.82 (2H, q, J=8 Hz), 3.54 (2H, s), 7.37 (3H, m), 7.51(1H, d, J=2 Hz), 7.80 (1H, brs), 8.03 (1H, br s); m/z (API⁺): 402, 404(M+H)⁺

EXAMPLE 10N-(2,4,4-Trimethyl-4H-isoquinolin-7-yl)-3-bromo-4-ethoxybenzamide

The amine hydrochloride D8 (226 mg, 1.0 mmol) in dichloromethane (10 ml)was sequentially treated with 3-bromo-4-ethoxybenzoyl chloride, (270 mg,1.0 mmol) and triethylamine (0.4 ml, 2.9 mmol). The mixture was stirredat 25° C. for 18 h and evaporated in vacuo. The resultant residue waspurified by chromatography on silica gel eluting withammonia:methanol:dichloromethane (0.5% 0.88 ammonia: 4.5% methanol: 95%dichloromethane). The title compound was obtained as an off-white foam(291 mg, 70%).

¹H NMR [free base](250 MHz, CDCl₃) δ: 1.30 (6H, s), 1.51 (3H, t, J=7Hz), 2.39 (2H, s), 2.41 (3H, s), 3.53 (2H, s), 4.17 (2H, q, J=7 Hz),6.93 (1H, d, J=9 Hz), 7.34 (3H, m), 7.65 (1H, brs), 7.80 (1H, dd, J=9, 2Hz), 8.04 (1H, d, J=2 Hz); m/z (API⁺): 418, 420 (M+H)⁺

A portion of the title compound was converted into the hydrochloridesalt.

¹H NMR (250 MHz, d⁶-DMSO) δ: 1.21 (3H, s), 1.28 (3H, t, J=7 Hz), 1.34(3H, s), 2.34-2.44 (2H, brs), 2.83 (3H, d, J=4 Hz), 4.10 (2H, q, J=7Hz), 4.15-4.37 (2H, m), 7.13 (1H, d, J=9 Hz), 7.37 (1H, d, J=8 Hz), 7.52(1H, brs), 7.54 (1H, d, J=9 Hz),), 7.89 (1H, dd, J=9, 2 Hz), 8.12 (1H,d, J=2 Hz),), 10.18 (1H, s), 10.35 (1H, brs).

EXAMPLE 11N-(2,4,4-Trimethyl-4H-isoquinolin-7-yl)-3-chloro--4-iso-propoxybenzamide

Prepared in a similar manner to Example 7, using3-chloro-4-iso-propoxybenzoyl chloride, and isolated in 84% yield.

¹H NMR (250 MHz, CDCl₃) δ: 1.30 (6H, s), 1.42 (6H, d, J=6 Hz), 2.39 (2H,s), 2.41 (3H, s), 3.53 (2H, s), 4.66 (1H, septet, J=6 Hz), 6.98 (1H, d,J=9 Hz), 7.35 (3H, m), 7.68 (1H, brs), 7.74 (1H, dd, J=9, 2 Hz), 7.87(1H, d, J=2 Hz). m/z (API⁺): 387, 389 (M+H)⁺

EXAMPLE 12 (±)N-(1,2-Dimethyl-4H-isoquinolin-7-yl)-3-bromo-4-ethylbenzamide

(±) 7-Amino-1,2-dimethyl-tetrahydroisoquinoline mono hydrochloride(0.106 g, 0.50 mmol) in dichloromethane (10 ml) was sequentially treatedwith 3-bromo-4-ethylbenzoyl chloride (0.124 g, 0.50 mmol) andtriethylamine (0.3 ml, 2.2 mmol). The mixture was stirred at ambienttemperature for 18 h. Evaporation in vacuo gave an oily residue whichwas purified by chromatography through silica gel eluting with (0.5%conc. ammonia: 4.5% methanol: 95% dichloromethane). The title compoundwas obtained as an off-white foam (0.149 g, 77%).

¹H NMR (250 MHz, CDCl₃) δ: 1.23 (3H, t, J=8 Hz), 1.36 (3H, d, J=7 Hz),2.46 (3H, s), 2.60(1H, m), 2.80 (4H, m), 3.54 (1H, q, J=7 Hz), 7.02 (1H,d, J=8 Hz), 7.25 (1H, d, J=8 Hz), 7.32 (1H, dd, J=8, 2 Hz), 8.00 (1H, d,J=2 Hz), 8.17 (1H, s); m/z (API): 387, 389 (M+H)⁺

EXAMPLE 13 (±)(N-(1,2-Dimethyl-4H-isoquinolin-7-yl)-3-bromo-4-ethoxybenzamide

Prepared as described in Example 12 using 3-bromo-4-ethoxybenzoylchloride and isolated in 90% yield.

¹H NMR (250 MHz, CDCl₃) δ: 1.36 (3H, d, J=7 Hz), 1.49 (3H, t, J=7 Hz),2.46 (3H, s), 2.64 (1H, m), 2.80 (2H, m), 3.00 (1H, m), 3.55 (1H, q, J=7Hz), 4.13 (2H, q, J=7 Hz), 6.85 (1H, d, J=9 Hz), 7.02 (1H, d, J=8 Hz),7.32 (1H, d, J=8, 2 Hz), 7.45 (1H, s), 7.77 (1H, dd, J=9, 2 Hz), 8.06(1H, s), 8.08 (1H, d, J=2 Hz); m/z (API): 403, 405 (M+H)⁺

EXAMPLE 14N-(1,1,2-Trimethyl-4H-isoquinolin-7-yl)-4-methoxy-3-trifuoromethylbenzamide

The title compound was prepared from7-amino-1,1,2-trimethyl-tetrahydroisoquinoline mono hydrochloride (0.077g, 0.3 mmol) and 3-trifluoromethyl-4-methoxybenzoyl chloride (0.083 g,0.3 mmol) in a manner similar to that of Example 12 as an off-white foam(0.132 g, 99%).

¹H NMR(250 MHz, CDCl₃) δ: 1.40 (6H, s), 2.44 (3H, s), 2.78-2.93 (4H, m),3.95 (3H, s), 7.00 (1H, s), 7.03 (1H, s), 7.33 (1H, dd, J=8, 2 Hz), 7.59(1H, d, J=2 Hz), 8.03-8.10 (3H, m); m/z (API): 393 (M+H)⁺

PHARMACOLOGICAL DATA

1. Binding Assay Method

WO 92/22293 (SmithKline Beecham) discloses compounds havinganti-convulsant activity, including inter alia the compoundtrans-(+)-6-acetyl-4S-(4-fluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3R-ol(hereinafter referred to as Compound A). It has been found that thecompounds of WO 92/22293 bind to a novel receptor obtainable from ratforebrain tissue, as described in WO 96/18650 (SmithKline Beecham). Theaffinity of test compounds to the novel receptor site is assessed asfollows.

Method

Whole forebrain tissue is obtained from rats. The tissue is firsthomogenised in buffer (usually 50 mM Tris/HCl, pH 7.4). The homogenisedtissue is washed by centrifugation and resuspension in the same buffer,then stored at −70° C. until used.

To carry out the radioligand binding assay, aliquots of tissue preparedas above (usually at a concentration of 1-2 mg protein/ml) are mixedwith aliquots of [3H]-Compound A dissolved in buffer. The finalconcentration of [3H]-Compound A in the mixture is usually 20 nM. Themixture is incubated at room temperature for 1 hour. [3H]-Compound Abound to the tissue is then separated from unbound [3H]-Compound A byfiltration through Whatman GF/B glass fibre filters. The filters arethen washed rapidly with ice-cold buffer. The amount of radioactivitybound to the tissue trapped on the filters is measured by addition ofliquid scintillation cocktail to the filters followed by counting in aliquid scintillation counter.

In order to determine the amount of “specific” binding of [3H]-CompoundA, parallel assays are carried out as above in which [3H]-Compound A andtissue are incubated together in the presence of unlabelled Compound A(usually 3 μM). The amount of binding of [3H]-Compound A remaining inthe presence of this unlabelled compound is defined as “non-specific”binding. This amount is subtracted from the total amount of[3H]-Compound A binding (i.e. that present in the absence of unlabelledcompound) to obtain the amount of “specific” binding of [3H]-Compound Ato the novel site.

The affinity of the binding of test compounds to the novel site can beestimated by incubating together [3H]-Compound A and tissue in thepresence of a range of concentrations of the compound to be tested. Thedecrease in the level of specific [3H]-Compound A binding as a result ofcompetition by increasing concentrations of the compound under test isplotted graphically, and non-linear regression analysis of the resultantcurve is used to provide an estimate of compound affinity in terms ofpKi value.

Results

Compounds of this invention were active in this test. For example,compounds of Examples 1 to 14 gave pKi values greater than 7.

2. MEST Test

The maximal electroshock seizure (MEST) threshold test in rodents isparticularly sensitive for detecting potential anticonvulsantproperties¹. In this model, anticonvulsant agents elevate the thresholdto electrically-induced seizures whilst proconvulsants lower the seizurethreshold.

Method for Mouse Model

Mice (naive male, Charles River, U.K. CD-1 strain, 25-30 g) are randomlyassigned to groups of 10-20 and dosed orally or intraperitoneally at adose volume of 10 ml/kg with various doses of compound (0.3-300 mg/kg)or vehicle. Mice are then subjected at 30 or 60 min post dose to asingle electroshock (0.1 sec, 50 Hz, sine wave form) administered viacorneal electrodes. The mean current and standard error required toinduce a tonic seizure in 50% (CC₅₀) of the mice in a particulartreatment group is determined by the ‘up and down’ method of Dixon andMood (1948)². Statistical comparisons between vehicle- and drug-treatedgroups are made using the method of Litchfield and Wilcoxon (1949)³.

In control animals the CC₅₀ is usually 14-18 mA. Hence the first animalin the control group is subjected to a current of 16 mA. If a tonicseizure does not ensue, the current is increased for a subsequent mouse.If a tonic convulsion does occur, then the current is decreased, and soon until all the animals in the group have been tested.

Studies are carried out using a Hugo Sachs Electronik Constant CurrentShock Generator with totally variable control of shock level from 0 to300 mA and steps of 2 mA are usually used.

Results

Compounds of this invention dosed at 10 mg/kg by the oral route as asuspension in methyl cellulose and tested one hour post dosing showed anincrease in seizure threshold. At a dose of 10 mg/kg/p.o. at 2 h, thecompounds of Examples 4, 5, and 6 showed percentage increases of 47, 46,and 36% respectively.

Method for Rat Model

The threshold for maximal (tonic hindlimb extension) electroshockseizures in male rats (Sprague Dawley, 80-150 g, 6 weeks old) wasdetermined by a Hugo Sachs Electronik stimulator which delivered aconstant current (0.3 sec duration; from 1-300 mA in steps of 5-20 mA).The procedure is similar to that outlined above for mouse and fulldetails are as published by Upton et al,.⁴

The percentage increase or decrease in CC₅₀ for each group compared tothe control is calculated.

Drugs are suspended in 1% methyl cellulose.

Results

At a dosage of 2 mg/kg p.o. at 2 h, the compounds of Examples 7 to 11show the increases set out in the Table.

TABLE pKI Rat MEST at Ex 2 mg/kg p.o at No Compound A 2h E7 8.5 510 E88.0 120 E9 8.3 53 E10 8.2 294 E11 7.9 204

References

1. Loscher, W. and Schmidt, D. (1988). Epilepsy Res., 2, 145-181

2. Dixon, W. J. and Mood, A. M. (1948). J. Amer. Stat. Assn., 43,109-126

3. Litchfield, J. T. and Wilcoxon, F.(1949). J. Pharmacol. exp. Ther.,96, 99-113

4. N. Upton, T. P. Blackburn, C. A. Campbell, D. Cooper, M. L. Evans, H.J. Herdon, P. D. King, A. M. Ray, T. O. Stean, W. N. Chan, J. M. Evansand M. Thompson. (1997). B. J. Pharmacol., 121, 1679-1686

What is claimed is:
 1. A compound ot formula (I) or pharmaceuticallyacceptable salt thereof:

where R¹ is hydrogen, C₁₋₆ alkyl (optionally substituted by hydroxy orC₁₋₄alkoxy), C₁₋₆alkenyl, C₁₋₆alkynyl, C₁₋₆alkylCO—, formyl, CF₃CO— orC₁₋₆alkylSO₂—, R² is hydrogen or up to three substituents selected fromhalogen, NO₂, CN, N₃, CF₃O—, CF₃S—, CF₃CO—, trifluoromethyldiazirinyl,C₁₋₆alkyl, C₁₋₆alkenyl, C₁₋₆alkynyl, C₁₋₆perfluoroalkyl,C₃₋₆-cycloalkyl, C₃₋₆-cycloalkyl-C₁₋₄alkyl-, C₁₋₆alkylO—, C₁₋₆alkylCO—,C₃₋₆-cycloalkylO—, C₃₋₆-cycloalkylCO—, C₃₋₆-cycloalkyl-C₁₋₄alkylO—,C₃₋₆-cycloalkyl-C₁₋₄alkylCO—, phenyl, phenoxy, benzyloxy, benzoyl,phenyl-C₁₋₄alkyl-, C₁₋₆alkylS—, C₁₋₆alkylSO₂—, (C₁₋₄alkyl)₂NSO₂—,(C₁₋₄alkyl)NHSO₂—, (C₁₋₄alkyl)₂NCO—, (C₁₋₄alkyl)NHCO— or CONH₂; or—NR⁵R⁶ where R⁵ is hydrogen or C₁₋₄ alkyl, and R⁶ is hydrogen,C₁₋₄alkyl, formyl, —CO₂C₁₋₄alkyl or —COC₁₋₄alkyl or two R² groupstogether form a carbocyclic ring that is saturated or unsaturated andunsubstituted or substituted by —OH or ═O; and the two R³ groups and thetwo R⁴ groups are each independently hydrogen or C₁₋₆ alkyl or the twoR³ groups and/or the two R⁴ groups together form a C₃₋₆ spiroalkyl groupprovided that at least one R³ or R⁴ group is not hydrogen; provided thatthe compound is not1-methyl-6-benzoylamino-1,2,3,4-tetrahydroisoquinoline, or1,2-dimethyl-6-benzoylamino-1,2,3,4-tetrahydroisoquinoline.
 2. Acompound according to claim 1 which has the formula (IA)

where R¹ is hydrogen, C₁₋₆ alkyl (optionally substituted by hydroxy orC₁₋₄alkoxy), C₁₋₆ alkenyl, C₁₋₆ alkynyl, formyl, C₁₋₆alkylCO,C₁₋₆alkylSO₂, or CF₃CO—; R²² is C₁₋₆alkylO—, C₃₋₆cycloalkylO— orC₃₋₆-cycloalkyl C₁₋₄alkylO—; R²³ is hydrogen, halogen, CN, N₃,trifluoromethyldiazirinyl, C₁₋₆perfluoroalkyl, CF₃O—, CF₃S—, CF₃CO—,C₁₋₆alkyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkyl-C₁₋₄alkyl-, C₁₋₆alkylO—,C₁₋₆alkylCO—, C₃₋₆cycloalkylCO—, C₃₋₆cycloalkyl-C₁₋₄alkylCO—, phenyl,phenoxy, benzyloxy, benzoyl, phenyl-C₁₋₄alkyl-, C₁₋₆alkylS—,C₁₋₆alkylSO₂—, (C₁₋₄alkyl)₂NSO₂, (C₁₋₄alkyl)NHSO₂, (C₁₋₄alkyl)₂NCO—,(C₁₋₄alkyl)NHCO— or CONH₂; R²⁴ is hydrogen, halogen, NO₂, CN, N₃,trifluoromethyldiazirinyl, C₁₋₆ alkylO—, C₁₋₆ alkylS—, C₁₋₆ alkyl,C₃₋₆cycloalkyl, C₃₋₆cycloalkyl-C₁₋₄alkyl-, C₁₋₆alkenyl, C₁₋₆alkynyl,CF₃CO—, C₁₋₆alkylCO—, C₃₋₆cycloalkylCO—, C₃₋₆cycloalkyl-C₁₋₄alkylCO—,phenyl, phenoxy, benzyloxy, benzoyl, phenyl-C₁₋₄alkyl-; or —NR⁵R⁶ whereR⁵ is hydrogen or C₁₋₄ alkyl, and R⁶ is hydrogen, C₁₋₄alkyl, formyl,—CO₂C₁₋₄alkyl or —COC₁₋₄alkyl; or R²³ and R²⁴together form a carbocyclicring that is unsaturated or saturated and unsubstituted or substitutedby carbonyl or hydroxyl; R⁴ is C₁₋₆ alkyl.
 3. A compound according toclaim 1 which has the formula (IB)

where R¹ is hydrogen, C₁₋₆ alkyl (optionally substituted by hydroxy orC₁₋₄alkoxy), C₁₋₆alkenyl, C₁₋₆alkynyl, C₁₋₆alkylCO—, formyl, CF₃CO— orC₁₋₆alkylSO₂—, R² is hydrogen or up to three substituents selected fromhalogen, NO₂, CN, N₃, CF₃O—, CF₃S—, CF₃CO—, trifluoromethyldiazirinyl,C₁₋₆alkyl, C₁₋₆alkenyl, C₁₋₆alkynyl, C₁₋₆perfluoroalkyl, C₃₋₆cycloalkyl,C₃₋₆cycloalkyl-C₁₋₄alkyl-, C₁₋₆alkylO—, C₁₋₆alkylCO—, C₃₋₆cycloalkylO—,C₃₋₆cycloalkylCO—, C₃₋₆cycloalkyl-C₁₋₄alkylO—,C₃₋₆cycloalkyl-C₁₋₄alkylCO—, phenyl, phenoxy, benzyloxy, benzoyl,phenyl-C₁₋₄alkyl-, C₁₋₆alkylS—, C₁₋₆alkylSO₂—, (C₁₋₄alkyl)NSO₂—,(C₁₋₄alkyl)NHSO₂—, (C₁₋₄alkyl)₂NCO—, (C₁₋₄alkyl)NHCO— or CONH₂; or—NR⁵R⁶ where R⁵ is hydrogen or C₁₋₄ alkyl, and R⁶ is hydrogen,C₁₋₄alkyl, formyl, —CO₂C₁₋₄alkyl or —COC₁₋₄alkyl; or two R² groupstogether form a carbocyclic ring that is saturated or unsaturated andunsubstituted or substituted by —OH or ═O; and each R³ is C₁₋₆ alkyl. 4.A compound according to claim 1 which has formula (IC)

where R¹ is hydrogen, C₁₋₆ alkyl (optionally substituted by hydroxy orC₁₋₄alkoxy), C₁₋₆alkenyl, C₁₋₆alkynyl, C₁₋₆alkylCO—, formyl, CF₃CO— orC₁₋₆alkylSO₂—, R² is hydrogen or up to three substituents selected fromhalogen, NO₂, CN, N₃, CF₃O—, CF₃S—, CF₃CO—, trifluoromethyldiazirinyl,C₁₋₆alkyl, C₁₋₆alkenyl, C₁₋₆alkynyl, C₁₋₆perfluoroalkyl, C₃₋₆cycloalkyl,C₃₋₆cycloalkyl-C₁₋₄alkyl-, C₁₋₆alkylO—, C₁₋₆alkylCO—, C₃₋₆cycloalkylO—,C₃₋₆cycloalkylCO—, C₃₋₆cycloalkyl-C₁₋₄alkylO—,C₃₋₆cycloalkyl-C₁₋₄alkylCO—, phenyl, phenoxy, benzyloxy, benzoyl,phenyl-C₁₋₄alkyl-, C₁₋₆alkylS—, C₁₋₆alkylSO₂—, (C₁₋₄alkyl)₂NSO₂—,(C₁₋₄alkyl)NHSO₂—, (C₁₋₄alkyl)₂NCO—, (C₁₋₄alkyl)NHCO— or CONH₂; or—NR⁵R⁶ where R⁵ is hydrogen or C₁₋₄ alkyl, and R⁶ is hydrogen,C₁₋₄alkyl, formyl, —CO₂C₁₋₄alkyl or —COC₁₋₄alkyl; or two R² groupstogether form a carbocyclic ring that is saturated or unsaturated andunsubstituted or substituted by —OH or ═O; and each R⁴ is C₁₋₆ alkyl. 5.A compound according to claim 1 selected from the group consisting of:(±)N-(1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl-5chloro-4-ethoxy-2-methoxybenzamide(±)N-(1,2-dimethyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-bromo-2,4-dimethoxybenzamide(±)N-(1,2-dimethyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-4-ethoxy-2-methoxybenzamide(±)N-(1,2-dimethyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-4-iso-propoxy-2-methoxybenzamide(±)N-(1,2-dimethyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-tert-butyl-2-methoxybenzamide(±)N-(1,2-dimethyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-trifluoromethyl-2-methoxy-4-methyl-benzamideN-(2,4,4-trimethyl-4H-isoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamideN-(2,4,4-trimethyl-4H-isoquinolin-7-yl)-3-cyano-4-iso-propylbenzamideN-(2,4,4,-trimethyl-4H-isoquinolin-7-yl)-3-bromo-4-ethylbenzamideN-(2,4,4-trimethyl-4H-isoquinolin-7-yl)-3-bromo-4-ethoxybenzamideN-(2,4,4-trimethyl-4H-isoquinolin-7-yl)-3-chloro-4-iso-propoxybenzamide(±) N-(1,2-dimethyl-4H-isoquinolin-7-yl)-3-bromo-4-ethylbenzamide (±)N-(1,2-dimethyl-4H-isoquinolin-7-yl)-3-bromo-4-ethoxybenzamideN-(1,1,2-trimethyl-4H-isoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide.6. A process for the preparation of compounds according to claim 1 whichcomprises reacting a compound of formula (II)

where R^(1A), R^(3A), R^(4A) are R¹, R³, R⁴ as defined for formula (I)or a group or groups convertible to R¹, R³, R⁴ with a compound offormula (III)

where Y is Cl or OH, and R^(2A) groups are independently R² as definedfor formula (I) or a group or groups convertible to R², and whererequired converting an R^(1A), R^(2A), R^(3A), R^(4A) group to a R¹, R²,R³, R⁴ group, converting one R¹, R², R³, R⁴ group to another R¹, R², R³,R⁴ group, or converting a salt product to the free base or anotherpharmaceutically acceptable salt, or separating any enantiomers, orconverting a free base product to a pharmaceutically acceptable salt. 7.A process for the preparation of compounds according to claim 2 whichcomprises reacting a compound of formula (II)

where R^(1A), R^(3A), R^(4A) are R¹, R³, R⁴ as defined for formula (I)or a group or groups convertible to R¹, R³, R⁴ with a compound offormula (III)

where Y is Cl or OH, and R^(2A) groups are independently R² as definedfor formula (I) or a group or groups convertible to R², and whererequired converting an R^(1A), R^(2A), R^(3A), R^(4A) group to a R¹, R²,R³, R⁴ group, converting one R¹, R², R³, R⁴ group to another R¹, R², R³,R⁴ group, or converting a salt product to the free base or anotherpharmaceutically acceptable salt, or separating any enantiomers, orconverting a free base product to a pharmaceutically acceptable salt. 8.A process for the preparation of compounds according to claim 3 whichcomprises reacting a compound of formula (II)

where R^(1A), R^(3A), R^(4A) are R¹, R³, R⁴ as defined for formula (I)or a group or groups convertible to R¹, R³, R⁴ with a compound offormula (III)

where Y is Cl or OH, and R^(2A) groups are independently R² as definedfor formula (I) or a group or groups convertible to R², and whererequired converting an R^(1A), R^(2A), R^(3A), R^(4A) group to a R¹, R²,R³, R⁴ group, converting one R¹, R², R³, R⁴ group to another R¹, R², R³,R⁴ group, or converting a salt product to the free base or anotherpharmaceutically acceptable salt, or separating any enantiomers, orconverting a free base product to a pharmaceutically acceptable salt. 9.A process for the preparation of compounds according to claim 4 whichcomprises reacting a compound of formula (II)

where R^(1A), R^(3A), R^(4A) are R¹, R³, R⁴ as defined for formula (I)or a group or groups convertible to R¹, R³, R⁴ with a compound offormula (III)

where Y is Cl or OH, and R^(2A) groups are independently R² as definedfor formula (I) or a group or groups convertible to R², and whererequired converting an R^(1A), R^(2A), R^(3A), R^(4A) group to a R¹, R²,R³, R⁴ group, converting one R¹, R², R³, R⁴ group to another R¹, R², R³,R⁴ group, or converting a salt product to the free base or anotherpharmaceutically acceptable salt, or separating any enantiomers, orconverting a free base product to a pharmaceutically acceptable salt.10. A process for the preparation of compounds according to claim 5which comprises reacting a compound of formula (II)

where R^(1A), R^(3A), R^(4A) are R¹, R³, R⁴ as defined for formula (I)or a group or groups convertible to R¹, R³, R⁴ with a compound offormula (III)

where Y is Cl or OH, and R^(2A) groups are independently R² as definedfor formula (I) or a group or groups convertible to R², and whererequired converting an R^(1A), R^(2A), R^(3A), R^(4A) group to a R¹, R²,R³, R⁴ group, converting one R¹, R², R³, R⁴ group to another R¹, R², R³,R⁴ group, or converting a salt product to the free base or anotherpharmaceutically acceptable salt, or separating any enantiomers, orconverting a free base product to a pharmaceutically acceptable salt.11. A pharmaceutical composition for use in the treatment and/orprophylaxis of anxiety, mania, depression, panic disorders and/oraggression, disorders associated with a subarachnoid hemorrhage orneural shock, the effects associated with withdrawal from cocaine,nicotine, alcohol, benzodiazepines and other substances of abuse,epilepsy, post-traumatic epilepsy and other disorders treatable and/orpreventable with anti-convulsive agents, Parkinson's disease, psychosis,migraine, cerebral ischaemia, Alzheimer's disease, Huntingdon's chorea,and other degenerative diseases, schizophrenia, obsessive compulsivedisorders (OCD), neurological deficits associated with AIDS, circadianrhythm disorders, insomnia, narcolepsy and other sleep disorders, Gilesde la Tourette's syndrome and other tics, traumatic brain injury,tinnitus, neuralgia, trigeminal neuralgia, neuropathic pain, dentalpain, cancer pain, inappropriate neuronal activity resulting inneurodysthesias, ataxias, muscular rigidity, temporomandibular jointdysfunction, or amyotrophic lateral sclerosis (ALS) which comprises acompound according to claim 1 and a pharmaceutically acceptable carrier.12. A method of treatment and/or prophylaxis of anxiety, mania,depression, panic disorders and/or aggression, disorders associated witha subarachnoid hemorrhage or neural shock, the effects associated withwithdrawal from cocaine, nicotine, alcohol, benzodiazepines and othersubstances of abuse, epilepsy, post-traumatic epilepsy and otherdisorders treatable and/or preventable with anti-convulsive agents,Parkinson's disease, psychosis, migraine, cerebral ischaemia,Alzheimer's disease, Huntingdon's chorea, and other degenerativediseases, schizophrenia, obsessive compulsive disorders (OCD),neurological deficits associated with AIDS, circadian rhythm disorders,insomnia, narcolepsy and other sleep disorders, Giles de la Tourette'ssyndrome and other tics, traumatic brain injury, tinnitus, neuralgia,trigeminal neuralgia, neuropathic pain, dental pain, cancer pain,inappropriate neuronal activity resulting in neurodysthesias, ataxias,muscular rigidity, temporomandibular joint dysfunction, or amyotrophiclateral sclerosis (ALS) comprising administering to the sufferer in needthereof an effective or prophylactic amount of a compound according toclaim
 1. 13. A pharmaceutical composition for use in the treatmentand/or prophylaxis of anxiety, mania, depression, panic disorders and/oraggression, disorders associated with a subarachnoid hemorrhage orneural shock, the effects associated with withdrawal from cocaine,nicotine, alcohol, benzodiazepines and other substances of abuse,epilepsy, post-traumatic epilepsy and other disorders treatable and/orpreventable with anti-convulsive agents, Parkinson's disease, psychosis,migraine, cerebral ischaemia, Alzheimer's disease, Huntingdon's chorea,and other degenerative diseases, schizophrenia, obsessive compulsivedisorders (OCD), neurological deficits associated with AIDS, circadianrhythm disorders, insomnia, narcolepsy and other sleep disorders, Gilesde la Tourette's syndrome and other tics, traumatic brain injury,tinnitus, neuralgia, triceminal neuralgia, neuropathic pain, dentalpain, cancer pain, inappropriate neuronal activity resulting inneurodysthesias, ataxias, muscular rigidity, temporomandibular jointdysfunction, or amyotrophic lateral sclerosis (ALS) which comprises acompound according to claim 2 and a pharmaceutically acceptable carrier.14. A pharmaceutical composition for use in the treatment and/orprophylaxis of anxiety, mania, depression, panic disorders and/oraggression, disorders associated with a subarachnoid hemorrhage orneural shock, the effects associated with withdrawal from cocaine,nicotine, alcohol, benzodiazepines and other substances of abuse,epilepsy, post-traumatic epilepsy and other disorders treatable and/orpreventable with anti-convulsive agents, Parkinson's disease, psychosis,migraine, cerebral ischaemia, Alzheimer's disease, Huntingdon's chorea,and other degenerative diseases, schizophrenia, obsessive compulsivedisorders (OCD), neurological deficits associated with AIDS, circadianrhythm disorders, insomnia, narcolepsy and other sleep disorders, Gilesde la Tourette's syndrome and other tics, traumatic brain injury,tinnitus, neuralgia, trigeminal neuralgia, neuropathic pain, dentalpain, cancer pain, inappropriate neuronal activity resulting inneurodysthesias, ataxias, muscular rigidity, temporomandibular jointdysfunction, or amyotrophic lateral sclerosis (ALS) which comprises acompound according to claim 3 and a pharmaceutically acceptable carrier.15. A pharmaceutical composition for use in the treatment and/orprophylaxis of anxiety, mania, depression, panic disorders and/oraggression, disorders associated with a subarachnoid hemorrhage orneural shock, the effects associated with withdrawal from cocaine,nicotine, alcohol, benzodiazepines and other substances of abuse,epilepsy, post-traumatic epilepsy and other disorders treatable and/orpreventable with anti-convulsive agents, Parkinson's disease, psychosis,migraine, cerebral ischaemia, Alzheimer's disease, Huntingdon's chorea,and other degenerative diseases, schizophrenia, obsessive compulsivedisorders (OCD), neurological deficits associated with AIDS, circadianrhythm disorders, insomnia, narcolepsy and other sleep disorders, Gilesde la Tourette's syndrome and other tics, traumatic brain injury,tinnitus, neuralgia, trigeminal neuralgia, neuropathic pain, dentalpain, cancer pain, inappropriate neuronal activity resulting inneurodysthesias, ataxias, muscular rigidity, temporomandibular jointdysfunction, or amyotrophic lateral sclerosis (ALS) which comprises acompound according to claim 4 and a pharmaceutically acceptable carrier.16. A pharmaceutical composition for use in the treatment and/orprophylaxis of anxiety, mania, depression, panic disorders and/oraggression, disorders associated with a subarachnoid hemorrhage orneural shock, the effects associated with withdrawal from cocaine,nicotine, alcohol, benzodiazepines and other substances of abuse,epilepsy, post-traumatic epilepsy and other disorders treatable and/orpreventable with anti-convulsive agents, Parkinson's disease, psychosis,migraine, cerebral ischaemia, Alzheimer's disease, Huntingdon's chorea,and other degenerative diseases, schizophrenia, obsessive compulsivedisorders (OCD), neurological deficits associated with AIDS, circadianrhythm disorders, insomnia, narcolepsy and other sleep disorders, Gilesde la Tourette's syndrome and other tics, traumatic brain injury,tinnitus, neuralgia, trigeminal neuralgia, neuropathic pain, dentalpain, cancer pain, inappropriate neuronal activity resulting inneurodysthesias, ataxias, muscular rigidity, temporomandibular jointdysfunction, or amyotrophic lateral sclerosis (ALS) which comprises acompound according to claim 5 and a pharmaceutically acceptable carrier.17. A method of treatment and/or prophylaxis of anxiety, mania,depression, panic disorders and/or aggression, disorders associated witha subarachnoid hemorrhage or neural shock, the effects associated withwithdrawal from cocaine, nicotine, alcohol, benzodiazepines and othersubstances of abuse, epilepsy, post-traumatic epilepsy and otherdisorders treatable and/or preventable with anti-convulsive agents,Parkinson's disease, psychosis, migraine, cerebral ischaemia,Alzheimer's disease, Huntingdon's chorea, and other degenerativediseases, schizophrenia, obsessive compulsive disorders (OCD),neurological deficits associated with AIDS, circadian rhythm disorders,insomnia, narcolepsy and other sleep disorders, Giles de la Tourette'ssyndrome and other tics, traumatic brain injury, tinnitus, neuralgia,trigeminal neuralgia, neuropathic pain, dental pain, cancer pain,inappropriate neuronal activity resulting in neurodysthesias, ataxias,muscular rigidity, temporomandibular joint dysfunction, or amyotrophiclateral sclerosis (ALS) comprising administering to the sufferer in needthereof an effective or prophylactic amount of a compound according toclaim
 2. 18. A method of treatment and/or prophylaxis of anxiety, mania,depression, panic disorders and/or aggression, disorders associated witha subarachnoid hemorrhage or neural shock, the effects associated withwithdrawal from cocaine, nicotine, alcohol, benzodiazepines and othersubstances of abuse, epilepsy, post-traumatic epilepsy and otherdisorders treatable and/or preventable with anti-convulsive agents,Parkinson's disease, psychosis, migraine, cerebral ischaemia,Alzheimer's disease, Huntingdon's chorea, and other degenerativediseases, schizophrenia, obsessive compulsive disorders (OCD),neurological deficits associated with AIDS, circadian rhythm disorders,insomnia, narcolepsy and other sleep disorders, Giles de la Tourette'ssyndrome and other tics, traumatic brain injury, tinnitus, neuralgia,trigeminal neuralgia, neuropathic pain, dental pain, cancer pain,inappropriate neuronal activity resulting in neurodysthesias, ataxias,muscular rigidity, temporomandibular joint dysfunction, or amyotrophiclateral sclerosis (ALS) comprising administering to the sufferer in needthereof an effective or prophylactic amount of a compound according toclaim
 3. 19. A method of treatment and/or prophylaxis of anxiety, mania,depression, panic disorders and/or aggression, disorders associated witha subarachnoid hemorrhage or neural shock, the effects associated withwithdrawal from cocaine, nicotine, alcohol, benzodiazepines and othersubstances of abuse, epilepsy, post-traumatic epilepsy and otherdisorders treatable and/or preventable with anti-convulsive agents,Parkinson's disease, psychosis, migraine, cerebral ischaemia,Alzheimer's disease, Huntingdon's chorea, and other degenerativediseases, schizophrenia, obsessive compulsive disorders (OCD),neurological deficits associated with AIDS, circadian rhythm disorders,insomnia, narcolepsy and other sleep disorders, Giles de la Tourette'ssyndrome and other tics, traumatic brain injury, tinnitus, neuralgia,trigeminal neuralgia, neuropathic pain, dental pain, cancer pain,inappropriate neuronal activity resulting in neurodysthesias, ataxias,muscular rigidity, temporomandibular joint dysfunction, or amyotrophiclateral sclerosis (ALS) comprising administering to the sufferer in needthereof an effective or prophylactic amount of a compound according toclaim
 4. 20. A method of treatment and/or prophylaxis of anxiety, mania,depression, panic disorders and/or aggression, disorders associated witha subarachnoid hemorrhage or neural shock, the effects associated withwithdrawal from cocaine, nicotine, alcohol, benzodiazepines and othersubstances of abuse, epilepsy, post-traumatic epilepsy and otherdisorders treatable and/or preventable with anti-convulsive agents,Parkinson's disease, psychosis, migraine, cerebral ischaemia,Alzheimer's disease, Huntingdon's chorea, and other degenerativediseases, schizophrenia, obsessive compulsive disorders (OCD),neurological deficits associated with AIDS, circadian rhythm disorders,insomnia, narcolepsy and other sleep disorders, Giles de la Tourettc'ssyndrome and other tics, traumatic brain injury, tinnitus, neuralgia,trigeminal neuralgia, neuropathic pain, dental pain, cancer pain,inappropriate neuronal activity resulting in neurodysthesias, ataxias,muscular rigidity, temporomandibular joint dysfunction, or amyotrophiclateral sclerosis (ALS) comprising administering to the sufferer in needthereof an effective or prophylactic amount of a compound according toclaim 5.